tbuckley/cabot-search huggingface dataset:
Formate Supplementation Enhances Antitumor CD8+ T-cell Fitness and Efficacy of PD-1 Blockade
Authors: Jared H. Rowe, Ilaria Elia, Osmaan Shahid, Emily F. Gaudiano, Natalia E. Sifnugel, Sheila Johnson, Amy G. Reynolds, Megan E. Fung, Shakchhi Joshi, Martin W. LaFleur, Joon Seok Park, Kristen E. Pauken, Joshua D. Rabinowitz, Gordon J. Freeman, Marcia C. Haigis, Arlene H. Sharpe
Journal: Cancer Discovery (2023)

Abstract The tumor microenvironment (TME) restricts antitumor CD8+ T-cell function and immunotherapy responses. Cancer cells compromise the metabolic fitness of CD8+ T cells within the TME, but the mechanisms are largely unknown. Here we demonstrate that one-carbon (1C) metabolism is enhanced in T cells in an antigen-specific manner. Therapeutic supplementation of 1C metabolism using formate enhances CD8+ T-cell fitness and antitumor efficacy of PD-1 blockade in B16-OVA tumors. Formate supplementation drives transcriptional alterations in CD8+ T-cell metabolism and increases gene signatures for cellular proliferation and activation. Combined formate and anti–PD-1 therapy increases tumor-infiltrating CD8+ T cells, which are essential for enhanced tumor control. Our data demonstrate that formate provides metabolic support to CD8+ T cells reinvigorated by anti–PD-1 to overcome a metabolic vulnerability in 1C metabolism in the TME to further improve T-cell function. Significance: This study identifies that deficiencies in 1C metabolism limit the efficacy of PD-1 blockade in B16-OVA tumors. Supplementing 1C metabolism with formate during anti–PD-1 therapy enhances CD8+ T-cell fitness in the TME and CD8+ T-cell–mediated tumor clearance. These findings demonstrate that formate supplementation can enhance exhausted CD8+ T-cell function. See related commentary by Lin et al., p. 2507. This article is featured in Selected Articles from This Issue, p. 2489
Exosome delivery to the testes for dmrt1 suppression: A powerful tool for sex-determining gene studies
Authors: Tengfei Zhu, Ming Kong, Yingying Yu, Manfred Schartl, Deborah Mary Power, Chen Li, Wenxiu Ma, Yanxu Sun, Shuo Li, Bowen Yue, Weijing Li, Changwei Shao
Journal: Journal of Controlled Release (2023)
Recent Secular Trends of Body Mass Index in Individuals With Bipolar Disorders and in the General Population
Authors: Hemen Najar, Erik Joas, Viktor Jonsson, Erik Pålsson, Mikael Landén
Journal: American Journal of Psychiatry (2023)

Objective: The aims of this study were to investigate secular trends and distribution of body mass index (BMI) among individuals with bipolar disorders and the general population between 2008 and 2019. Methods: Data were from the Swedish National Quality Register for Bipolar Disorder, where 24,423 adults with bipolar disorders were identified, and from the national Swedish Living Conditions Surveys, where 77,485 adults from the general population were identified. Quantile regression was used to compare the 15th, 50th, and 85th percentiles of BMI across age and study years. Results: The study sample included 22,127 individuals with bipolar disorders (mean age, 48 years; 63% women) and 71,894 individuals from the general population (mean age, 52 years; 51% women). BMI percentiles were higher among individuals with bipolar disorders. At the 50th percentile, the BMI group differences were 1.1 (95% CI=0.8–1.14) for men and 1.8 (95% CI=1.5–2.1) for women. The gap was widest at the 85th BMI percentile: men, 2.3 (95% CI=1.8–2.8); women, 4.1 (95% CI=3.7–4.6). BMI increased over time in both study groups, but more in the group with bipolar disorders. The changes per decade in mean BMI were 0.4 (95% CI=0.3–0.5) among men in the general population, 1.1 (95% CI=0.7–1.4) among men with bipolar disorders, 0.6 (95% CI=0.5–0.7) among women in the general population, and 1.4 (95% CI=1.1–1.7) among women with bipolar disorders. Women with bipolar disorders had the highest prevalence and the greatest rate of increase of obesity. In 2019, the obesity prevalence was 33% among women and 29% among men with bipolar disorders, compared with 13% and 15%, respectively, among women and men in the general population. Conclusions: Adults with bipolar disorders had a higher BMI and a higher prevalence of obesity than the general population, indicating a higher cardiometabolic risk. Annually, BMI increased more in the group with bipolar disorders than in the general population, particularly among women and among those with high BMI.
Tumor-Infiltrating Normal B Cells Revealed by Immunoglobulin Repertoire Clonotype Analysis Are Highly Prognostic and Crucial for Antitumor Immune Responses in DLBCL
Authors: Zijun Y. Xu-Monette, Yong Li, Thomas Snyder, Tiantian Yu, Tingxun Lu, Alexandar Tzankov, Carlo Visco, Govind Bhagat, Wenbin Qian, Karen Dybkaer, April Chiu, Wayne Tam, Youli Zu, Eric D. Hsi, Fredrick B. Hagemeister, Yingjun Wang, Heounjeong Go, Maurilio Ponzoni, Andrés J.M. Ferreri, Michael B. Møller, Benjamin M. Parsons, Xiangshan Fan, J. Han van Krieken, Miguel A. Piris, Jane N. Winter, Qingyan Au, Ilan Kirsch, Mingzhi Zhang, John Shaughnessy, Bing Xu, Ken H. Young
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Tumor-infiltrating B lymphocytes (TIL-B) have demonstrated prognostic and predictive significance in solid cancers. In this study, we aimed to distinguish TIL-Bs from malignant B-cells in diffuse large B-cell lymphoma (DLBCL) and determine the clinical and biological significance. Experimental Design: A total of 269 patients with de novo DLBCL from the International DLBCL R-CHOP Consortium Program were studied. Ultra-deep sequencing of the immunoglobulin genes was performed to determine B-cell clonotypes. The frequencies and numbers of TIL-B clonotypes in individual repertoires were correlated with patient survival, gene expression profiling (GEP) data, and frequencies of DLBCL-infiltrating immune cells quantified by fluorescent multiplex IHC at single-cell resolution. Results: TIL-B abundance, evaluated by frequencies of normal B-cell clonotypes in the immunoglobulin repertoires, remarkably showed positive associations with significantly better survival of patients in our sequenced cohorts. DLBCLs with high versus low TIL-B abundance displayed distinct GEP signatures, increased pre-memory B-cell state and naïve CD4 T-cell state fractions, and higher CD4+ T-cell infiltration. TIL-B frequency, as a new biomarker in DLBCL, outperformed the germinal center (GC) B-cell–like/activated B-cell–like classification and TIL-T frequency. The identified TIL-B–high GEP signature, including genes upregulated during T-dependent B-cell activation and those highly expressed in normal GC B cells and T cells, showed significant favorable prognostic effects in several external validation cohorts. Conclusions: TIL-B frequency is a significant prognostic factor in DLBCL and plays a crucial role in antitumor immune responses. This study provides novel insights into the prognostic determinants in DLBCL and TIL-B functions with important therapeutic implications.
A Randomized Controlled Neuroimaging Trial of Cognitive Behavioral Therapy for Fibromyalgia Pain
Authors: Jeungchan Lee, Asimina Lazaridou, Myrella Paschali, Marco L. Loggia, Michael P. Berry, Dan‐Mikael Ellingsen, Kylie Isenburg, Alessandra Anzolin, Arvina Grahl, Ajay D. Wasan, Vitaly Napadow, Robert R. Edwards
Journal: Arthritis & Rheumatology (2023)

Objective Fibromyalgia (FM) is characterized by pervasive pain‐related symptomatology and high levels of negative affect. Mind–body treatments such as cognitive behavioral therapy (CBT) appear to foster improvement in FM via reductions in pain‐related catastrophizing, a set of negative, pain‐amplifying cognitive and emotional processes. However, the neural underpinnings of CBT's catastrophizing‐reducing effects remain uncertain. This randomized controlled mechanistic trial was designed to assess CBT's effects on pain catastrophizing and its underlying brain circuitry. Methods Of 114 enrolled participants, 98 underwent a baseline neuroimaging assessment and were randomized to 8 weeks of individual CBT or a matched FM education control (EDU) condition. Results Compared with EDU, CBT produced larger decreases in pain catastrophizing post treatment ( P &lt; 0.05) and larger reductions in pain interference and symptom impact. Decreases in pain catastrophizing played a significant role in mediating those functional improvements in the CBT group. At baseline, brain functional connectivity between the ventral posterior cingulate cortex (vPCC), a key node of the default mode network (DMN), and somatomotor and salience network regions was increased during catastrophizing thoughts. Following CBT, vPCC connectivity to somatomotor and salience network areas was reduced. Conclusion Our results suggest clinically important and CBT‐specific associations between somatosensory/motor‐ and salience‐processing brain regions and the DMN in chronic pain. These patterns of connectivity may contribute to individual differences (and treatment‐related changes) in somatic self‐awareness. CBT appears to provide clinical benefits at least partially by reducing pain‐related catastrophizing and producing adaptive alterations in DMN functional connectivity.
Three‐Dimensional Chromosomal Landscape Revealing <scp>miR</scp>‐146a Dysfunctional Enhancer in Lupus and Establishing a <scp>CRISPR‐Mediated</scp> Approach to Inhibit the Interferon Pathway
Authors: Xinyi Zhu, Yutong Zhang, Zihang Yin, Zhizhong Ye, Yuting Qin, Zhaorui Cheng, Yiwei Shen, Zhihua Yin, Jianyang Ma, Yuanjia Tang, Huihua Ding, Ya Guo, Guojun Hou, Nan Shen
Journal: Arthritis & Rheumatology (2023)

The diminished expression of microRNA-146a (miR-146a) in systemic lupus erythematosus (SLE) contributes to the aberrant activation of the interferon pathway. Despite its significance, the underlying mechanism driving this reduced expression remains elusive. Considering the integral role of enhancers in steering gene expression, our study seeks to pinpoint the SLE-affected enhancers responsible for modulating miR-146a expression. Additionally, we aim to elucidate the mechanisms by which these enhancers influence the contribution of miR-146a to the activation of the interferon pathway.
Identifying biomarkers of heterogeneity and transplantation efficacy in retinal pigment epithelial cells
Authors: Farhad Farjood, Justine D. Manos, Yue Wang, Anne L. Williams, Cuiping Zhao, Susan Borden, Nazia Alam, Glen Prusky, Sally Temple, Jeffrey H. Stern, Nathan C. Boles
Journal: The Journal of Experimental Medicine (2023)

Transplantation of retinal pigment epithelial (RPE) cells holds great promise for patients with retinal degenerative diseases, such as age-related macular degeneration. In-depth characterization of RPE cell product identity and critical quality attributes are needed to enhance efficacy and safety of replacement therapy strategies. Here, we characterized an adult RPE stem cell–derived (RPESC-RPE) cell product using bulk and single-cell RNA sequencing (scRNA-seq), assessing functional cell integration in vitro into a mature RPE monolayer and in vivo efficacy by vision rescue in the Royal College of Surgeons rats. scRNA-seq revealed several distinct subpopulations in the RPESC-RPE product, some with progenitor markers. We identified RPE clusters expressing genes associated with in vivo efficacy and increased cell integration capability. Gene expression analysis revealed lncRNA (TREX) as a predictive marker of in vivo efficacy. TREX knockdown decreased cell integration while overexpression increased integration in vitro and improved vision rescue in the RCS rats.
6 Years Out, Nivo–Ipi Looks Solid in NSCLC
Journal: Cancer Discovery (2023)

According to the latest update from CheckMate 227 Part 1, at 6 years' minimum follow-up, nivolumab combined with ipilimumab continues to outperform chemotherapy up front for advanced non-small cell lung cancer in terms of overall survival. Dual immune checkpoint inhibition induced greater tumor shrinkage, and these deep responses strongly correlated with long-term OS benefit.
Non‐cardiac comorbidities and intensive up‐titration of oral treatment in patients recently hospitalized for heart failure: Insights from the <scp>STRONG‐HF</scp> trial
Authors: Ovidiu Chioncel, Beth Davison, Marianna Adamo, Laura E. Antohi, Mattia Arrigo, Marianela Barros, Jan Biegus, Kamilė Čerlinskaitė‐Bajorė, Jelena Celutkiene, Alain Cohen‐Solal, Albertino Damasceno, Rafael Diaz, Christopher Edwards, Gerasimos Filippatos, Antoine Kimmoun, Carolyn S.P. Lam, Marco Metra, Maria Novosadova, Matteo Pagnesi, Peter S. Pang, Piotr Ponikowski, Razvan I. Radu, Hadiza Saidu, Karen Sliwa, Adriaan A. Voors, Koji Takagi, Jozine M. Ter Maaten, Daniela Tomasoni, Gad Cotter, Alexandre Mebazaa
Journal: European Journal of Heart Failure (2023)
Women in STEM becoming independent: Great mentors make all the difference
Authors: Lucie Van Emmenis
Journal: The Journal of Experimental Medicine (2023)

In this Viewpoint, we hear from a cross section of women, across multiple research fields, discussing their science and the process of setting up a lab as an independent researcher. As well as being able to celebrate the positives of becoming an independent researcher, we would also like to use this platform to discuss the unique challenges they face as women scientists in their respective scientific environments.
The economic cost of obstructive sleep apnea: A systematic review
Authors: Ida Alakörkkö, Soili Törmälehto, Timo Leppänen, Walter T. McNicholas, Erna S. Arnardottir, Reijo Sund
Journal: Sleep Medicine Reviews (2023)

Obstructive sleep apnea (OSA) is a common disease associated with a high prevalence of costly comorbidities and accidents that add to the disease's economic impact. Although more attention has been focused on OSA in recent years, no previous systematic reviews have synthesized findings from existing studies that provide estimates of the economic cost of OSA. This study aims to summarize the findings of existing studies that provide estimates of the cost of OSA. Two bibliographic databases, PubMed and Scopus, were used to identify articles on the costs of OSA. The systematic literature review identified 5,938 publications, of which 31 met the inclusion criteria. According to the results, adjusted for inflation and converted to euros, the annual cost per patient ranged from €236 (the incremental cost of OSA) for New Zealand to €28,267 for the United States. The total annual cost per patient in Europe ranged from €1,669 to €5,186. OSA causes a significant burden on society, and OSA-related costs increase many years before the diagnosis and remain elevated for a long time after the diagnosis. Despite some well-conducted studies, the cost estimates for OSA are uncertain and specific to the context in which the study was conducted.
METTL5-mediated 18S rRNA m6A modification promotes oncogenic mRNA translation and intrahepatic cholangiocarcinoma progression
Authors: Zihao Dai, Wanjie Zhu, Yingdong Hou, Xinyue Zhang, Xuxin Ren, Kai Lei, Junbin Liao, Haining Liu, Zhihang Chen, Sui Peng, Shaoqiang Li, Shuibin Lin, Ming Kuang
Journal: Molecular Therapy (2023)

Intrahepatic cholangiocarcinoma (ICC) is a deadly cancer with rapid tumor progression. While hyperactive mRNA translation caused by mis-regulated mRNA or tRNA modifications promotes ICC development, the role of rRNA modifications remains elusive. Here, we found that 18S rRNA m
Safety of surfactant excipients in oral drug formulations
Authors: Sam Maher, Caroline Geoghegan, David J. Brayden
Journal: Advanced Drug Delivery Reviews (2023)

Surfactants are a diverse group of compounds that share the capacity to adsorb at the boundary between distinct phases of matter. They are used as pharmaceutical excipients, food additives, emulsifiers in cosmetics, and as household/industrial detergents. This review outlines the interaction of surfactant-type excipients present in oral pharmaceutical dosage forms with the intestinal epithelium of the gastrointestinal (GI) tract. Many surfactants permitted for human consumption in oral products reduce intestinal epithelial cell viability in vitro and alter barrier integrity in epithelial cell monolayers, isolated GI tissue mucosae, and in animal models. This suggests a degree of mis-match for predicting safety issues in humans from such models. Recent controversial preclinical research also infers that some widely used emulsifiers used in oral products may be linked to ulcerative colitis, some metabolic disorders, and cancers. We review a wide range of surfactant excipients in oral dosage forms regarding their interactions with the GI tract. Safety data is reviewed across in vitro, ex vivo, pre-clinical animal, and human studies. The factors that may mitigate against some of the potentially abrasive effects of surfactants on GI epithelia observed in pre-clinical studies are summarised. We conclude with a perspective on the overall safety of surfactants in oral pharmaceutical dosage forms, which has relevance for delivery system development.
Developing a Continuous Severity Scale for Macular Telangiectasia Type 2 Using Deep Learning and Implications for Disease Grading
Authors: Yue Wu, Catherine Egan, Abraham Olvera-Barrios, Lea Scheppke, Tunde Peto, Peter Charbel Issa, Tjebo F.C. Heeren, Irene Leung, Anand E. Rajesh, Adnan Tufail, Cecilia S. Lee, Emily Y. Chew, Martin Friedlander, Aaron Y. Lee
Journal: Ophthalmology (2023)
Type 2 Diabetes — Controlling the Epidemic, Episode 2: After the Diagnosis — Making a Plan and Addressing Social Determinants of Health
Authors: E Dale Abel, Julie R Ingelfinger, Joshua Kolko, Suyanna Linhales Barker, Dinora Lopez, Mirna Mejia, Monica Peek, Jane E B Reusch, Clifford J Rosen
Journal: New England Journal of Medicine (2023)

In this second episode of "Type 2 Diabetes — Controlling the Epidemic," a four-part Double Take video miniseries from the New England Journal of Medicine, Drs. Jane E.B. Reusch (University of Colorado), E. Dale Abel (UCLA), and Monica Peek (University of Chicago) describe the process of tailoring type 2 diabetes interventions and education to the individual patient. The video also highlights the impact that health inequities can have on diabetes management. For further reading, the following articles, referenced in this video, are available on the Journal's website: Beyond Diversity — Time for New Models of Health (Delgado, in the February 10, 2022, issue), Community Health Workers and Covid-19 — Addressing Social Determinants of Health in Times of Crisis and Beyond (Peretz et al., in the November 5, 2020, issue), and Race in Medicine — Genetic Variation, Social Categories, and Paths to Health Equity (Evans et al., in the September 30, 2021, issue).
From Ashes to Action — Indigenous Health Perspectives on the Lāhainā Fires
Authors: Kekoa Taparra, Mālia Purdy, Kalani L. Raphael
Journal: New England Journal of Medicine (2023)

Interview with Kekoa Taparra on the Lāhainā fires and persistent threats to community recovery. (09:44)Download Historical oppression fueled both the Lāhainā fires and the health inequities faced by Native Hawaiian communities. Healing and rebuilding should be shaped by community voices and perspectives.
Dabrafenib plus Trametinib in Pediatric Glioma with <i>BRAF</i> V600 Mutations
Authors: Eric Bouffet, Jordan R. Hansford, Maria Luisa Garrè, Junichi Hara, Ashley Plant-Fox, Isabelle Aerts, Franco Locatelli, Jasper van der Lugt, Ludmila Papusha, Felix Sahm, Uri Tabori, Kenneth J. Cohen, Roger J. Packer, Olaf Witt, Larissa Sandalic, Ana Bento Pereira da Silva, Mark Russo, Darren R. Hargrave
Journal: New England Journal of Medicine (2023)

Detection of the BRAF V600E mutation in pediatric low-grade glioma has been associated with a lower response to standard chemotherapy. In previous trials, dabrafenib (both as monotherapy and in combination with trametinib) has shown efficacy in recurrent pediatric low-grade glioma with BRAF V600 mutations, findings that warrant further evaluation of this combination as first-line therapy. In this phase 2 trial, patients with pediatric low-grade glioma with BRAF V600 mutations who were scheduled to receive first-line therapy were randomly assigned in a 2:1 ratio to receive dabrafenib plus trametinib or standard chemotherapy (carboplatin plus vincristine). The primary outcome was the independently assessed overall response (complete or partial response) according to the Response Assessment in Neuro-Oncology criteria. Also assessed were the clinical benefit (complete or partial response or stable disease for ≥24 weeks) and progression-free survival. A total of 110 patients underwent randomization (73 to receive dabrafenib plus trametinib and 37 to receive standard chemotherapy). At a median follow-up of 18.9 months, an overall response occurred in 47% of the patients treated with dabrafenib plus trametinib and in 11% of those treated with chemotherapy (risk ratio, 4.31; 95% confidence interval [CI], 1.7 to 11.2; P<0.001). Clinical benefit was observed in 86% of the patients receiving dabrafenib plus trametinib and in 46% receiving chemotherapy (risk ratio, 1.88; 95% CI, 1.3 to 2.7). The median progression-free survival was significantly longer with dabrafenib plus trametinib than with chemotherapy (20.1 months vs. 7.4 months; hazard ratio, 0.31; 95% CI, 0.17 to 0.55; P<0.001). Grade 3 or higher adverse events occurred in 47% of the patients receiving dabrafenib plus trametinib and in 94% of those receiving chemotherapy. Among pediatric patients with low-grade glioma with BRAF V600 mutations, dabrafenib plus trametinib resulted in significantly more responses, longer progression-free survival, and a better safety profile than standard chemotherapy as first-line therapy. (Funded by Novartis; ClinicalTrials.gov number, NCT02684058.).
Effectiveness of Smallpox Vaccination to Prevent Mpox in Military Personnel
Authors: Boghuma K Titanji, Angelia Eick-Cost, Elizabeth S Partan, Lauren Epstein, Natalie Wells, Shauna L Stahlman, Poornima Devineni, Brigid Munyoki, Saiju Pyarajan, Abirami Balajee, Jeremy Smith, Chris W Woods, Mark Holodniy, Victoria J Davey, Robert A Bonomo, Yinong Young-Xu, Vincent C Marconi
Journal: New England Journal of Medicine (2023)
Case 29-2023: A 34-Year-Old Woman with Abdominal Distention and Acute Kidney Injury
Authors: Sundar Jagannath, Mark A. Anderson, Andrew J. Yee, Robert P. Hasserjian
Journal: New England Journal of Medicine (2023)

A 34-year-old woman was admitted to the hospital because of abdominal distention, fatigue, and acute kidney injury that occurred 10 months after orthotopic liver transplantation. A diagnosis was made.
Mechanical Power and Ventilator-induced Lung Injury: What Does Physics Have to Say?
Authors: Jason H. T. Bates, David W. Kaczka, Michaela Kollisch-Singule, Gary F. Nieman, Donald P. Gaver
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

"Mechanical Power and Ventilator-induced Lung Injury: What Does Physics Have to Say?." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp.
Inhaled Fluticasone Furoate for Outpatient Treatment of Covid-19
Authors: David R. Boulware, Christopher J. Lindsell, Thomas G. Stewart, Adrian F. Hernandez, Sean Collins, Matthew William McCarthy, Dushyantha Jayaweera, Nina Gentile, Mario Castro, Mark Sulkowski, Kathleen McTigue, G. Michael Felker, Adit A. Ginde, Sarah E. Dunsmore, Stacey J. Adam, Allison DeLong, George Hanna, April Remaly, Florence Thicklin, Rhonda Wilder, Sybil Wilson, Elizabeth Shenkman, Susanna Naggie
Journal: New England Journal of Medicine (2023)

The effectiveness of inhaled glucocorticoids in shortening the time to symptom resolution or preventing hospitalization or death among outpatients with mild-to-moderate coronavirus disease 2019 (Covid-19) is unclear.